US20160362436A1 - Sialic acid derivatives - Google Patents
Sialic acid derivatives Download PDFInfo
- Publication number
- US20160362436A1 US20160362436A1 US15/121,585 US201515121585A US2016362436A1 US 20160362436 A1 US20160362436 A1 US 20160362436A1 US 201515121585 A US201515121585 A US 201515121585A US 2016362436 A1 US2016362436 A1 US 2016362436A1
- Authority
- US
- United States
- Prior art keywords
- group
- diyl
- formula
- alkyl
- sialic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical class CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 title claims abstract description 70
- -1 hydrocarbon radical Chemical class 0.000 claims description 481
- 150000001875 compounds Chemical class 0.000 claims description 64
- 229920006395 saturated elastomer Polymers 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 53
- 150000003254 radicals Chemical class 0.000 claims description 49
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 40
- 125000004432 carbon atom Chemical group C* 0.000 claims description 36
- 201000010099 disease Diseases 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000002950 monocyclic group Chemical group 0.000 claims description 23
- 239000000651 prodrug Substances 0.000 claims description 21
- 229940002612 prodrug Drugs 0.000 claims description 21
- 239000004215 Carbon black (E152) Substances 0.000 claims description 15
- 150000001768 cations Chemical class 0.000 claims description 15
- 229930195733 hydrocarbon Natural products 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 208000035475 disorder Diseases 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 108010047827 Sialic Acid Binding Immunoglobulin-like Lectins Proteins 0.000 claims description 13
- 102000007073 Sialic Acid Binding Immunoglobulin-like Lectins Human genes 0.000 claims description 13
- 239000003446 ligand Substances 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 208000023275 Autoimmune disease Diseases 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 206010020751 Hypersensitivity Diseases 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 8
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 230000007815 allergy Effects 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 210000000987 immune system Anatomy 0.000 claims description 8
- 125000004954 trialkylamino group Chemical group 0.000 claims description 8
- 230000003844 B-cell-activation Effects 0.000 claims description 7
- 206010033892 Paraplegia Diseases 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 150000001540 azides Chemical class 0.000 claims description 7
- 208000037976 chronic inflammation Diseases 0.000 claims description 7
- 230000006020 chronic inflammation Effects 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 230000028993 immune response Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 230000003612 virological effect Effects 0.000 claims description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 229910004749 OS(O)2 Inorganic materials 0.000 claims description 6
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 6
- 210000004369 blood Anatomy 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 230000003394 haemopoietic effect Effects 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 230000003071 parasitic effect Effects 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 5
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 5
- 230000033228 biological regulation Effects 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005277 alkyl imino group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 4
- 230000001180 sulfating effect Effects 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000001348 pyrrole-2,5-diyl group Chemical group N1C(=CC=C1*)* 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims 3
- 238000003379 elimination reaction Methods 0.000 claims 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- 239000000243 solution Substances 0.000 description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 49
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
- 0 [1*][C@]1(CC)O[C@@H]([C@@]([5*])([H])[C@@]([6*])([H])CN([H])CC)[C@H]([4*])[C@@H](C)[C@]1([2*])[3*] Chemical compound [1*][C@]1(CC)O[C@@H]([C@@]([5*])([H])[C@@]([6*])([H])CN([H])CC)[C@H]([4*])[C@@H](C)[C@]1([2*])[3*] 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 20
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 20
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 20
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 13
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 201000003874 Common Variable Immunodeficiency Diseases 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- HYXRUZUPCFVWAH-UHFFFAOYSA-N ethyl 6-hydroxyhexanoate Chemical compound CCOC(=O)CCCCCO HYXRUZUPCFVWAH-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
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- 208000030507 AIDS Diseases 0.000 description 5
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- 108010029157 Sialic Acid Binding Ig-like Lectin 2 Proteins 0.000 description 5
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- 239000002253 acid Substances 0.000 description 5
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 208000029138 selective IgA deficiency disease Diseases 0.000 description 5
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- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- 206010001935 American trypanosomiasis Diseases 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 208000024699 Chagas disease Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 241000223109 Trypanosoma cruzi Species 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
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- 239000001301 oxygen Substances 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 125000005629 sialic acid group Chemical group 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- 238000002255 vaccination Methods 0.000 description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
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- 125000004559 acridin-9-yl group Chemical group C1=CC=CC2=NC3=CC=CC=C3C(=C12)* 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
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- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
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- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 description 1
- 125000004540 benzothiazol-5-yl group Chemical group S1C=NC2=C1C=CC(=C2)* 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- YOUGRGFIHBUKRS-UHFFFAOYSA-N benzyl(trimethyl)azanium Chemical compound C[N+](C)(C)CC1=CC=CC=C1 YOUGRGFIHBUKRS-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004556 carbazol-9-yl group Chemical group C1=CC=CC=2C3=CC=CC=C3N(C12)* 0.000 description 1
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- 125000001485 cycloalkadienyl group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
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- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000001543 furan-2,5-diyl group Chemical group O1C(=CC=C1*)* 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 150000004761 hexafluorosilicates Chemical class 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
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- 125000004536 indazol-1-yl group Chemical group N1(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000004245 indazol-3-yl group Chemical group [H]N1N=C(*)C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000004537 indazol-5-yl group Chemical group N1N=CC2=CC(=CC=C12)* 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 description 1
- 125000004247 indolizin-1-yl group Chemical group [H]C1=C([H])C(*)=C2C([H])=C([H])C([H])=C([H])N12 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000004252 isoindol-1-yl group Chemical group [H]N1C([H])=C2C([H])=C([H])C([H])=C([H])C2=C1* 0.000 description 1
- 125000004254 isoquinolin-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C2C(*)=N1 0.000 description 1
- 125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000005246 nonafluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000007793 ph indicator Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000004557 phenoxazin-10-yl group Chemical group C1=CC=CC=2OC3=CC=CC=C3N(C12)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- KOODSCBKXPPKHE-UHFFFAOYSA-N propanethioic s-acid Chemical compound CCC(S)=O KOODSCBKXPPKHE-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000004257 pteridin-2-yl group Chemical group [H]C1=C([H])N=C2C([H])=NC(*)=NC2=N1 0.000 description 1
- 125000004258 purin-2-yl group Chemical group [H]N1C2=NC(*)=NC([H])=C2N([H])C1([H])[H] 0.000 description 1
- 125000004542 purin-6-yl group Chemical group N1=CN=C2N=CNC2=C1* 0.000 description 1
- 125000004543 purin-7-yl group Chemical group N1=CN=C2N=CN(C2=C1)* 0.000 description 1
- 125000004544 purin-8-yl group Chemical group N1=CN=C2N=C(NC2=C1)* 0.000 description 1
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 description 1
- 125000004547 quinazolin-6-yl group Chemical group N1=CN=CC2=CC(=CC=C12)* 0.000 description 1
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
- 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 description 1
- 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 description 1
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 description 1
- 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 description 1
- 125000004553 quinoxalin-5-yl group Chemical group N1=CC=NC2=C(C=CC=C12)* 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 1
- 125000005537 sulfoxonium group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 238000007794 visualization technique Methods 0.000 description 1
- 125000004333 xanthen-1-yl group Chemical group [H]C1=C([H])C2=C(C([H])=C1[H])C([H])([H])C1=C(*)C([H])=C([H])C([H])=C1O2 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
Abstract
Description
- The invention relates to derivatives of sialic acid, to processes for preparing them, to their use, especially as active pharmaceutical ingredients, and also to pharmaceutical active ingredient compositions which comprise such compounds.
- Sialic acid is the generic term for a family of 9-carbon atom sugars which represent all derivatives of neuramic acid (Neu) and of keto-deoxy-nonulosonic acid (KDN). They are typically located at the exposed, non-reducing ends of oligosaccharide chains. Sialic acids play multivarious roles in mammals and in the human body (Schauer (2004) Zoology, 107, 49-64; Varki (2008) Trends in Mol. Med., 14, 8, 351-360). Furthermore, they are utilized by many pathogens in order, for example, to achieve efficient infection or in order to evade the immune system of the host (Glycoconjugate J. 2006, vol. 23, issue 1-2, all articles). Many such functions are regulated via proteins which recognize sialic acids (Lehmann et al. (2006) Cell-Mol. Life Sci. 63, 1331-1354).
- One subgroup of such proteins are the Siglecs. They are lectins of the Ig type which are characterized by an N-terminal V-set domain, which allows specific recognition of sialic acids. A review of the types of Siglec proteins hitherto disclosed, and of diseases potentially treatable using Siglec inhibitors, is found in Trends in “Pharmacological Sciences 2009, 30 (5), 240-248” and “Current Medicinal Chemistry 2011, 18, 3537-3550” and in the references therein.
- CD22 (Siglec-2) is highly expressed in B cells. It is known that disorders based on B cells, especially lymphomas and autoimmune diseases, can be treated by means of CD22 ligands (Tedder et al. (2005) Advances in Immunology 88, 1-50; Fiorina et al. (2008) Diabetes 57, 3013-3024).
- Furthermore, antibodies and polymeric sialic acids have already been developed as ligands with therapeutic suitability for Siglec-2 (Courtney et al. (2009) PNAS 106, 8, 2500-505; Collins et al. (2006) Journal of Immunology 177, 2994-3003). The polymers have the disadvantage of very high molecular weight, an undefinable and non-uniform size and composition.
- It is known that certain monomeric derivatives of sialic acid with substitutions at position C-9 (WO 03/000709 and J. Exp. Med. 2002, 195, 9, 1207-1213), and also with substitutions at C-9, C-5 and C-2 (Chem Med Chem 2012, 7, 134-143), act as ligands for CD22 and have potential suitability as medicaments. It is also known that sialic acid derivatives with substitutions at C-9 and C-4 and with a methoxy group at C-2 (Angewandte Chemie Int. Ed., 2013, 53, 3616-3620) have increased affinity for Siglec-2.
- Dimeric derivatives of sialic acid are known from WO 2013/190103 and WO 2013/097942.
- Although the known derivatives already have high affinities, there is nevertheless a broad room for improvements, especially with regard to affinity and selectivity. In addition, there is room for improvements in pharmacological tolerability and administration forms and also in stability in plasma and liver.
- It is an object of the invention to provide compounds with which advantages are achieved within parts at least of the stated areas.
- It has been found that certain monomeric sialic acid derivatives, with a nitrogen substituted in the 9-position and with further substituents at the 4- and 2-positions, are particularly suitable as Siglec-2 (CD22) ligands.
- The invention accordingly provides a sialic acid derivative of the formula (I),
- where the symbols have the following definitions:
- A1 is a group D1-[Y2-D2-]m;
- D1 is a mono- or polycyclic aromatic, partially unsaturated or saturated C3-C14 hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to twelve-membered heterocyclic radical, the stated radicals being unsubstituted or substituted one or more times by a group X;
- D2 is a mono- or polycyclic aromatic, partially unsaturated or saturated C3-C14 hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, the stated radicals being unsubstituted or substituted one or more times by a group X;
- Y1 is ˜C(O)—, ˜S(O)2—, ˜NHC(O)—, ˜(C1-C2 alkyl)-, ˜(C1-C2 alkyl)-C(O)—, ˜CH═CH—C(O)—, ˜C≡C—C(O)—, ˜(C1-C2 alkyl)-S(O)2—, ˜OC(O)—, ˜(C1-C2 alkyl)-OC(O)— or ˜(C1-C2 alkyl)-NHC(O)—, where ˜ denotes the bond to the group A1;
- Y2 is —O—, —C(O)—, —S(O)2—, —CH2— or a bond;
- A2 is
- a) a group —OS(O)2OL or
- b) a group —N(Rx)—W;
- W is
- a) a group ˜SO3L, ˜SO2CF3 or ˜SO2NRx 2 or
- b) a group D3-Y3—;
- Y3 is a bond or a group ˜O(CO)NHS(O)2—, ˜NHC(O)—, ˜OC(O)—, ˜CH2OC(O)—, ˜S(O)2—, ˜C(O)—, ˜(C1-C2 alkyl)-C(O)—, ˜(C1-C2 alkyl)-NHC(O)— or ˜(C1-C2 alkyl)-S(O)2—, where ˜ denotes the bond to the group D3;
- D3 is
- a) C1-C6 alkyl, where optionally one or more non-terminal CH2 groups are replaced by O, N(Rx) and/or C(O), and where optionally one or more H atoms in the stated groups are replaced by a group X, or
- b) is a mono- or polycyclic aromatic, partially unsaturated or saturated C3-C14 hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, the stated radicals being unsubstituted or substituted one or more times by a group X;
- A3 is
- a) a C1-C8 alkyl, where optionally
- a. one or more non-terminal —CH2— groups are replaced by S, O, N(Rx) and/or C(O), or
- b. a —CH2CH2CH2— group is replaced by 1,2-phenyldiyl, 1,3-phenyldiyl or 1,4-phenyldiyl, and where optionally one or more H atoms in the stated groups are replaced by a group X, or
- b) is a mono- or polycyclic aromatic, partially unsaturated or saturated C3-C14 hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, the stated radicals being unsubstituted or substituted one or more times by a group X;
- X is identically or differently halogen, cyano, nitro, hydroxyl, mercapto, amino, carboxyl, carboxymethyl, hydroxylamino, azido, B(OH2), SO, SO3M, OSO3M, SO2NH2, SO2CF3, PO3M, OPO3M, cyanomethyl, alkyl, haloalkyl, alkyloxy, haloalkyloxy, alkylamino, dialkylamino, trialkylamino, formyl, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, dialkylaminocarbonyl, oxo (═O), thioxo (═S), C1-C8 alkylimino (═N—C1-C8 alkyl) or C1-C8 alkyloximino (═N—O—C1-C8 alkyl), the alkyl groups in these radicals containing 1 to 6 carbon atoms;
- m is 0, 1 or 2;
- Z is ˜O—, ˜S—, —ON═CH˜, ˜ON(Rx)—, ˜N(Rx)— or ˜4-1H-(1,2,3)triazol-1-yl-, where ˜ denotes the bond to the group A3;
- R1 is C(O)OM;
- R2 is H, F, Cl, NRx or ORx;
- R3 is H, F, Cl, NRx ORx;
- R4 is N(Rx)C(O)CH2OH or N(Rx)C(O)Rx;
- R5, R6 are identically or differently OH or ORx;
- L is a cation;
- M is C1-C4 alkyl or a cation;
- Rx is identically or differently H, Ry or Rz;
- Ry is identically or differently C1-C4 alkyl, phenyl or benzyl, and
- Rz is identically or differently —C(O)—C1-C4 alkyl, —C(O)-phenyl or C(O)—CH2-phenyl.
- Likewise provided by the invention is a pharmaceutical preparation comprising at least one sialic acid derivative of the formula (I) or a pharmacologically tolerated salt or prodrug thereof, and a pharmacologically tolerated carrier.
- Additionally provided by the invention, moreover, is a sialic acid derivative of the formula (I) or a pharmacologically tolerated salt or prodrug thereof, as medicament.
- By way of example, modifications to individual substituents in pharmacologically active molecules, to form prodrug forms, are described in Nature Drug Discovery Reviews, 2008, 7, 255-270 and in Hydrolysis in Drug and Prodrug Metabolism, Wiley-VCH, 2003, Bernard Testa and Joachim M. Mayer.
- The invention also provides a sialic acid derivative of the formula (I), or a pharmacologically tolerated salt or prodrug thereof, for the treatment or prevention of allergies, autoimmune disorders, chronic inflammations, paraplegia, multiple sclerosis, cancer, viral disorders, for example AIDS, bacterial disorders, for example streptococci, parasitic disorders, for example Chagas disease, diseases in which the immune response is disrupted in the context of B cell activation, such as Common Variable Immunodeficiency (CVID) and IgA deficiency, in diseases of the hematopoietic organs and of the blood, and also in cancer, for example lymphomas and myelomas, and also for the regulation of the immune system, for example in the case of vaccinations.
- Further provided by the invention is a sialic acid derivative of the formula (I), or a pharmacologically tolerated salt or prodrug thereof, for use in the production of a medicament for the regulation of the immune system, for example in the case of vaccinations, and also for the treatment of allergies, autoimmune disorders, chronic inflammations, paraplegia, multiple sclerosis, cancer, viral disorders, for example AIDS, bacterial disorders, for example streptococci, parasitic disorders, for example Chagas disease, diseases in which the immune response is disrupted in the context of B cell activation, such as Common Variable Immunodeficiency (CVID) and IgA deficiency, in diseases of the hematopoietic organs and of the blood, and also in cancer, for example lymphomas and myelomas.
- Likewise provided by the invention is a method for regulating the immune system, for example in the case of vaccinations, and also for the treatment of diseases whose course or activity can be influenced by the Siglec ligands, more particularly from the group of allergies, autoimmune disorders, chronic inflammations, paraplegia, multiple sclerosis, cancer, viral disorders, for example AIDS, bacterial disorders, for example streptococci, parasitic disorders, for example Chagas disease, diseases in which the immune response is disrupted in the context of B cell activation, such as Common Variable Immunodeficiency (CVID) and IgA deficiency, in diseases of the hematopoietic organs and of the blood, and also in cancer, for example lymphomas and myelomas, in which a person affected by the disease is administered a preferably therapeutically effective amount of a sialic acid derivative of the formula (I) or of a pharmacologically tolerated salt or prodrug thereof.
- The sialic acid derivatives of the formula (I) exhibit a significantly increased affinity in comparison to hitherto-disclosed monovalent CD22 ligands. Even at low concentrations, they influence the calcium excretion of B cells in vitro.
- Through the combination of substituents C-9 and C-4 of the sialic acid framework with methoxy substituents of C-2 that are larger than that already known, an unexpectedly greatly increased affinity for CD22 has been achieved. This is so particularly against the background that for another member of the Siglec family (MAG or Siglec-4), the combination of substituents at positions C-9, C-4 and C-2 resulted in a lowering of the affinity (Carbohydrate Research, 2010, 345, 1348-1359). The sialic acid derivatives of the formula (I) have a high activity for CD22 and, in contrast to polymers, have an unambiguous and definable structure in each case. In comparison with other high-affinity, dimeric CD22 ligands known to date, they have a significantly reduced molecular weight. Apart from sialic acid, moreover, they contain no further carbohydrates and can be modified to form prodrugs in a simple way. The compounds are prepared without using cell cultures or enzymes, thus enabling production on the industrial scale.
- The term “sialic acid derivative of the formula (I)” encompasses all stereoisomeric forms of the compound of the formula (I), especially E/Z or cis/trans isomers in the case of substituted double bonds or rings, and also stereoisomers resulting from the centers of chirality in the compounds of the formula (I), more particularly enantiomers and diastereoisomers, in pure form or in the form of mixtures of any composition, with the individual centers of chirality present in each case in the (S)- or (R)-form.
- The individual stereoisomers may be prepared, for example, by enrichment of the isomeric mixtures in accordance with customary techniques, such as chromatography or crystallization, or by use of isomerically pure starting materials. The enrichment of the isomers may take place at the stage of the reactants, intermediates or end products of the formula (I). The isomers encompassed in accordance with the invention also include all tautomeric forms of compounds (I), and all mesomorphous forms.
- Furthermore, the term “sialic acid derivative of the formula (I)” encompasses solvates, examples being hydrates or adducts with alcohols, and also all crystal modifications.
- The invention also provides pharmacologically effective metabolites of the compounds (I). More particularly the term “metabolites” encompasses cleavage products generated by enzymes that occur “in vivo”, such as esterases, amidases and other enzymes.
- Furthermore, the term “sialic acid derivatives of the formula (I)” encompasses pharmacologically tolerated salts of the compounds (I), including internal salts (zwitterions).
- Generally speaking, the salts contemplated are the salts of those cations, or the acid addition salts of those acids, whose cations or anions, respectively, do not adversely affect the pharmacological activity of the compounds (I).
- Cations contemplated include, in particular, ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium and magnesium, and of the transition metals, preferably manganese, copper, zinc and iron, and also ammonium, in which case, if desired, one to four hydrogen atoms may be replaced by RY, preferably ammonium, dimethylammonium, diisopropylammonium, tetramethylammonium, triethylammonium, tetrabutylammonium, 2-(2-hydroxyeth-1-oxy)eth-1-ylammonium, di(2-hydroxyeth-1-yl)ammonium, trimethylbenzylammonium, and also phosphonium ions, sulfonium ions, preferably tri(C1-C4 alkyl)sulfonium, and sulfoxonium ions, preferably tri(C1-C4 alkyl)sulfoxonium. Preferred are Na, Li, K, Ca, Mg and ammonium (optionally substituted); particularly preferred are Na, Li and K; especially preferred is Na.
- Anions of pharmacologically tolerated acid addition salts are, for example, chloride, bromide, fluoride, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, nitrate, hydrogencarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, the anions of C1-C4 alkanoic acids, preferably formate, acetate, propionate and butyrate, and of other organic acids, such as pivalic acid, maleic acid, succinic acid, pimelic acid, fumaric acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, citric acid and adipic acid.
- Unless otherwise indicated, symbols which are used more than once may have the same or different definitions independently of one another.
- The definitions of the symbols indicated in the formula (I) are as follows:
- halogen (halo): fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo);
- alkyl: saturated, straight-chain, branched or cyclic hydrocarbon radicals having for example 1 to 8 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2,2-dimethylcyclopropyl, 2,3-dimethylcyclopropyl, cyclohexyl and cyclooctyl;
- haloalkyl: straight-chain, branched or cyclic alkyl groups having for example 1 to 6 carbon atoms (as specified above), some or all of the hydrogen atoms in these groups having been replaced by halogen atoms: such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1-fluoro-1-methylethyl, 1-fluorocyclopropyl, heptafluoropropyl or nonafluorobutyl;
- alkyloxy: alkyloxy groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 6 carbon atoms;
- haloalkyloxy: haloalkyloxy groups with a straight-chain, branched or cyclic haloalkyl radical, this radical being from the above-stated group of the haloalkyls, and containing 1 to 6 carbon atoms;
- alkylamino: alkylamino groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- dialkylamino: dialkylamino groups with saturated, straight-chain, branched or cyclic alkyl radicals, these radicals being, identically or differently, from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- trialkylamino: trialkylamino groups with saturated, straight-chain, branched or cyclic alkyl radicals, these radicals being, identically or differently, from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkylcarbonyl: alkylcarbonyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkylsulfonyl: alkylsulfonyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkylsulfoxyl: alkylsulfoxyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkylaminosulfonyl: alkylaminosulfonyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- dialkylaminosulfonyl: dialkylaminosulfonyl groups with saturated, straight-chain, branched or cyclic alkyl radicals, these radicals being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkyloxycarbonyl: alkyloxycarbonyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkylcarbonyloxy: alkylcarbonyloxy groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkylaminocarbonyl: alkylaminocarbonyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- dialkylaminocarbonyl: dialkylaminocarbonyl groups with saturated, straight-chain, branched or cyclic alkyl radicals, these radicals being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkylimino: alkylimino groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkyloximino: alkyloximino groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkylcarbonylamino: alkylcarbonylamino groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms.
- The skilled person is aware that a cyclic or branched alkyl group has at least three carbon atoms. In accordance with the invention, the term “alkyl” is also used for alkylene groups (alkanediyl groups). This is evident from the context in each case.
- Mono- or polycyclic, aromatic, partially unsaturated or saturated C3-C14 hydrocarbon radical for D2 denotes, for example:
- a) C6-C14 aryldiyl, more particularly phenylene-1,4-diyl, phenylene-1,3-diyl, phenylene-1,2-diyl, naphthalene-1,2-diyl, naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-1,8-diyl, naphthalene-2,3-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl, biphenylene-1,2-diyl, biphenylene-1,3-diyl, biphenylene-1,4-diyl, biphenylene-1,5-diyl, biphenylene-1,6-diyl, biphenylene-1,7-diyl, biphenylene-1,8-diyl, biphenylene-2,3-diyl, biphenylene-2,6-diyl and biphenylene-2,7-diyl;
- b) C3-C8 cycloalkyldiyl, more particularly trans-cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, trans-cyclobutane-1,3-diyl, cis-cyclobutane-1,3-diyl, trans-cyclopentane-1,3-diyl, cis-cyclohexane-1,4-diyl, trans-cyclohexane-1,4-diyl, trans-cycloheptane-1,4-diyl, trans-cyclooctane-1,5-diyl and cubane-1,4-diyl.
- Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical for D2 denotes, for example:
- a) non-aromatic, saturated or partially unsaturated 5- or 6-membered heterocyclodiyl, containing one to three nitrogen atoms and/or one oxygen or sulfur atom or one or two oxygen and/or sulfur atoms, more particularly trans-tetrahydrofuran-2,5-diyl, trans-tetrahydrofuran-2,4-diyl, cis-tetrahydrofuran-2,5-diyl, trans-tetrahydrothiene-2,5-diyl, trans-tetrahydrothiene-2,4-diyl, trans-pyrrolidine-2,5-diyl, trans-pyrrolidine-2,4-diyl, isoxazolidine-2,4-diyl, isoxazolidine-2,5-diyl, isothiazolidine-2,4-diyl, isothiazolidine-2,5-diyl, pyrazolidine-1,3-diyl, trans-oxazolidine-2,4-diyl, trans-thiazolidine-2,5-diyl, imidazolidine-1,3-diyl, trans-imidazolidine-2,4-diyl, pyrroline-1,3-diyl, trans-pyrroline-2,4-diyl, trans-pyrroline-2,5-diyl, trans-piperidine-2,5-diyl, piperidine-1,4-diyl, trans-dioxane-2,5-diyl, trans-tetrahydropyrane-2,5-diyl, trans-hexahydropyridazine-3,6-diyl, trans-hexahydropyridazine-1,4-diyl, trans-hexahydropyrimidine-2,5-diyl, hexahydropyrimidine-1,3-diyl, hexahydropyrimidine-1,4-diyl, piperazine-1,4-diyl, trans-piperazine-2,5-diyl and piperazine-1,3-diyl;
- b) 5-membered heteroaryldiyl, containing one to four nitrogen atoms or one to three nitrogen atoms and/or one sulfur or oxygen atom, more particularly furan-2,4-diyl, furan-2,5-diyl, thiophene-2,4-diyl, thiophene-2,5-diyl, pyrrole-2,4-diyl, pyrrole-2,5-diyl, pyrazole-1,3-diyl, oxazole-2,4-diyl, oxazole-2,5-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, 1,2,4-thiadiazole-3,5-diyl, 1,3,4-thiadiazole-2,5-diyl, isooxazole-3,5-diyl, thiazole-2,4-diyl, thiazole-2,5-diyl, isothiazole-3,5-diyl, imidazole-2,4-diyl, 2H-tetrazole-2,5-diyl, 1H(1,2,4)triazole-2,5-diyl, 1H(1,2,3)triazole-1,4-diyl, and 1H-(1,2,3)triazole-1,5-diyl;
- c) 6-membered heteroaryldiyl, containing one to three or one to four nitrogen atoms, more particularly pyridine-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridazine-3,6-diyl, pyrimidine-2,5-diyl, pyrimidine-2,6-diyl, pyrazine-2,5-diyl and tetrazine-3,5-diyl.
- Polycyclic aromatic, partially unsaturated or saturated heterocyclic radical for D2 denotes, for example:
- 1-benzofuran-4,7-diyl, 1-benzofuran-2,7-diyl, 2-benzofuran-4,7-diyl, 2-benzofuran-3,6-diyl, chromene-5,8-diyl, chromene-3,7-diyl, xanthene-1,4-diyl, xanthene-2,6-diyl, indazole-4,7-diyl, purine-2,8-diyl, 4H-quinolizine-6,9-diyl, 3-isoquinoline-1,4-diyl, phthalazine-1,4-diyl, 1,8-naphthyridine-2,6-diyl, quinoxaline-2,6-diyl, quinazoline-5,8-diyl, cinnoline-5,8-diyl, pteridine-2,6-diyl, indolizine-2,6-diyl, indole-4,7-diyl, indole-2,5-diyl, indole-3,6-diyl, isoindole-4,7-diyl, isoindole-2,5-diyl, carbazole-1,4-diyl, acridine-1,4-diyl, phenoxazine-1,4-diyl, benzoxazole-4,7-diyl, benzothiazole-4,7-diyl, benzoimidazole-4,7-diyl, 1H-benzotriazole-4,7-diyl and benzothiophenediyl.
- Mono- or polycyclic, aromatic, partially unsaturated or saturated C3-C14 hydrocarbon radical for D1, D3 and A3 denotes, for example:
- a) C6-C14 aryl, more particularly phenyl, 1-naphthyl, 2-naphthyl, 1-biphenylene, 2-biphenylene, 1-pyrenyl, 1-anthracenyl, 2-anthracenyl, 9-anthracenyl, 4-indenyl, 2-fluorenyl, 3-fluorenyl, 9-fluorenyl and 3-phenanthrenyl;
- b) C3-C14 cycloalkenyl or C5-C14 cycloalkadienyl, more particularly cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadien-1-yl, cyclohexadien-1-yl and cyclooctadien-1-yl;
- c) C3-C8 cycloalkyl, more particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-1-yl, cuban-1-yl, bicyclo[4.4.0]decan-2-yl and cyclooctyl.
- Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical for D1, D3 and A3 denotes, for example:
- a) non-aromatic, saturated or partially unsaturated 4-, 5-, 6- or 7-membered heterocyclyl, containing one to four nitrogen atoms and/or one oxygen or sulfur atom or one or two oxygen and/or sulfur atoms, more particularly 1-aza-2-oxocyclobut-1-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 4,5-dihydro-1,3-oxazol-2-yl, 4,5-dihydro-1,3-oxazol-4-yl, 4,5-dihydro-1,3-oxazol-5-yl, 4,5-dihydro-1,3-thiazol-2-yl, 4,5-dihydro-1,3-thiazol-4-yl, 4,5-dihydro-1,3-thiazol-5-yl, 4,5-dihydro-4H-1,3-oxazin-2-yl, 4,5-dihydro-4H-1,3-thiazin-2-yl, 4,5,6,7-tetrahydro-1,3-oxazepin-2-yl, 4,5,6,7-tetrahydro-1,3-thiazepin-2-yl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-morpholinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 5H-tetrazol-5-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, 1-piperazinyl and 2-piperazinyl;
- b) 5-membered heteroaryl, containing one to four nitrogen atoms or one to three nitrogen atoms and/or one sulfur or oxygen atom: more particularly 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-isoxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,5-thiadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,3,4-thiatriazol-5-yl, 1H-(1,2,3)triazol-1-yl, 1H-(1,2,3)triazol-4-yl, 1H-(1,2,3)triazol-5-yl, 1H-(1,3,4)triazol-1-yl and 1H-(1,3,4)triazol-2-yl;
- c) 6-membered heteroaryl, containing one to three or one to four nitrogen atoms: more particularly 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.
- Polycyclic aromatic, partially unsaturated or saturated heterocyclic radical for D1, D3 and A3 denotes, for example:
- 1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-5-yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl, 2-benzofuran-1-yl, 2-benzofuran-3-yl, 2-benzofuran-4-yl, 2-benzofuran-5-yl, 2-benzofuran-6-yl, 2-benzofuran-7-yl, 2H-chromen-3-yl, 2H-chromen-4-yl, 2H-chromen-5-yl, 2H-chromen-6-yl, 2H-chromen-7-yl, 2H-chromen-8-yl, xanthen-1-yl, xanthen-4-yl, xanthen-9-yl, indazol-1-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, purin-2-yl, purin-6-yl, purin-7-yl, purin-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, phthalazin-1-yl, phthalazin-3-yl, phthalazin-5-yl, phthalazin-6-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 1,8-naphthyridin-6-yl, 1,8-naphthyridin-7-yl, quinoxalin-2-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinazolin-4-yl, quinazolin-6-yl, cinnolin-3-yl, cinnolin-4-yl, cinnolin-6-yl, pteridin-2-yl, pteridin-4-yl, pteridin-6-yl, pteridin-7-yl, indolizin-1-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl, indol-6-yl, indol-7-yl, indol-8-yl, isoindol-1-yl, isoindol-2-yl, isoindol-4-yl, isoindol-5-yl, carbazol-9-yl, acridin-9-yl, phenoxazin-10-yl, 1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl, 1-benzothiophen-8-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzimidazol-8-yl, 1H-benzotriazol-1-yl, 1H-benzotriazol-5-yl, 1H-benzotriazol-6-yl, 1H-benzotriazol-7-yl, 1H-benzotriazol-8-yl, 4H-3,1-benzoxazin-2-yl, 4H-2-benzopyran-2-yl, 2H-isoquinolin-3-yl, benzothiazol-2-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl, benzothiazol-8-yl, benzoxazol-2-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl or benzoxazol-8-yl.
- The stated linear or cyclic hydrocarbon radicals and heterocycles may be unsubstituted or substituted, the substituents being selected preferably from the group X. Preferred, depending on the respective chain size or ring size, are 1, 2, 3 or 4 substituents; in the case of halogen substituents, preference is also given to substitution up to the maximum possible number (persubstitution).
- The symbols in the formula (I) advantageously have the following definitions:
- A1 is advantageously a group D1-[Y2-D2-]m-.
- D1 is advantageously a mono- or polycyclic aromatic or saturated C3-C14 hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, the stated radicals being unsubstituted or substituted one or more times by a group X.
- D2 is advantageously a group phenylene-1,4-diyl, phenylene-1,3-diyl, pyridine-2,5-diyl, pyridazine-3,6-diyl, pyrimidine-2,5-diyl, pyrimidine-2,6-diyl, pyrazine-2,5-diyl, trans-cyclobutane-1,3-diyl, trans-cyclopentane-1,3-diyl, trans-cyclohexane-1,4-diyl, cubane-1,4-diyl, thiophene-2,5-diyl, pyrrole-2,4-diyl, pyrrole-2,5-diyl, pyrazole-1,3-diyl, oxazole-2,4-diyl, oxazole-2,5-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, isooxazole-3,5-diyl, imidazole-2,4-diyl, 2H-tetrazole-2,5-diyl, 1H(1,2,4)-triazole-2,5-diyl, 1H(1,2,3)-triazole-1,4-diyl and 1H(1,2,3)-triazole-1,5-diyl, the stated radicals being unsubstituted or substituted one or more times by a group X.
- Y1 is advantageously ˜C(O)—, ˜S(O)2—, ˜NHC(O)—, ˜CH2C(O)—, ˜CH2—S(O)2—, ˜OC(O)—, ˜CH2—OC(O)— or ˜CH2NHC(O)—, where ˜ denotes the bond to the group A1.
- Y2 is advantageously —O—, —CH2— or a bond.
- A2 is advantageously
- a) a group —OS(O)2OL or
- b) a group —N(Rx)—W.
- W is advantageously
- a) a group ˜SO3L, ˜SO2CF3 or ˜SO2NRx 2 or
- b) a group D3-Y3—.
- Y3 is advantageously a bond or a group ˜NHC(O)—, ˜OC(O)—, ˜CH2OC(O)—, ˜S(O)2, ˜C(O)—, ˜CH2—C(O)—, ˜CH2—NHC(O)— or ˜CH2—S(O)2—, where ˜ denotes the bond to the group D3.
- D3 is advantageously
- a) a C1-C6 alkyl, where optionally one or more non-terminal CH2 groups are replaced by O and where optionally one or more H atoms in the stated groups are replaced by a group X,
- b) a monocyclic or polycyclic aromatic or saturated C3-C14 hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, the stated radicals being unsubstituted or substituted one or more times by a group X.
- A3 is advantageously a C3-C8 alkyl, where optionally
- a. one or more non-terminal —CH2— groups are replaced by S or O, or
- b. a —CH2CH2CH2— group is replaced by 1,2-phenyldiyl, 1,3-phenyldiyl or 1,4-phenyldiyl, and where optionally one or more H atoms in the stated groups are replaced by a group X;
- X is advantageously identically or differently halogen, hydroxyl, amino, carboxyl, carboxymethyl, SO3M, OSO3M, SO2NH2, SO2CF3, alkyl, haloalkyl, alkyloxy, alkylamino, dialkylamino, trialkylamino, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkylaminocarbonyl, alkylcarbonylamino or oxo (═O), the alkyl groups in these radicals containing 1 to 3 carbon atoms.
- m is 0 or 1.
- Z is advantageously ˜O—, ˜S— or ˜4-1H-(1,2,3)triazol-1-yl-, where ˜ denotes the bond to the group A3.
- R1 is advantageously C(O)OM.
- R2 is advantageously H or F.
- R3 is advantageously H, F, Cl or ORx.
- R4 is advantageously NHC(O)CH2OH or NHC(O)CH3.
- R5, R6 are advantageously identically or differently OH or ORZ.
- L is advantageously a cation.
- M is advantageously a C1-C3 alkyl or a cation.
- Rx is advantageously identically or differently H, Ry or Rz.
- Ry is advantageously identically or differently C1-C3 alkyl, phenyl or benzyl.
- Rz is advantageously identically or differently —C(O)—C1-C3 alkyl or —C(O)-phenyl.
- The meanings of the definitions of the symbols as indicated in the formula (I) are advantageously as follows:
- halogen (halo): fluorine (fluoro), chlorine (chloro) and bromine (bromo);
- alkyl: saturated, straight-chain, branched or cyclic hydrocarbon radicals having for example 1 to 8 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2,2-dimethylcyclopropyl, 2,3-dimethylcyclopropyl, cyclohexyl and cyclooctyl;
- haloalkyl: straight-chain, branched or cyclic alkyl groups having for example 1 to 3 carbon atoms (as specified above), some or all of the hydrogen atoms in these groups having been replaced by halogen atoms: such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1-fluoro-1-methylethyl, 1-fluorocyclopropyl or heptafluoropropyl;
- alkyloxy: alkyloxy groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 3 carbon atoms;
- alkylamino: alkylamino groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 2 carbon atoms;
- dialkylamino: dialkylamino groups with saturated, straight-chain, branched or cyclic alkyl radicals, these radicals being, identically or differently, from the above-stated group of the alkyls, and containing 1 to 2 carbon atoms;
- trialkylamino: trialkylamino groups with saturated, straight-chain, branched or cyclic alkyl radicals, these radicals being, identically or differently, from the above-stated group of the alkyls, and containing 1 to 2 carbon atoms;
- alkylsulfonyl: alkylsulfonyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 4 carbon atoms;
- alkylaminosulfonyl: alkylaminosulfonyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 3 carbon atoms;
- alkyloxycarbonyl: alkyloxycarbonyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 3 carbon atoms;
- alkylcarbonyloxy: alkylcarbonyloxy groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 3 carbon atoms;
- alkylaminocarbonyl: alkylaminocarbonyl groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 3 carbon atoms;
- alkylcarbonylamino: alkylcarbonylamino groups with a saturated, straight-chain, branched or cyclic alkyl radical, this radical being from the above-stated group of the alkyls, and containing 1 to 3 carbon atoms.
- Mono- or polycyclic, aromatic or saturated C3-C14 hydrocarbon radical for D1 and D3 denotes, for example:
- a) C6-C14 aryl, more particularly phenyl, naphth-1-yl, naphth-2-yl, biphen-4-yl, biphen-2-yl, anthracen-9-yl, inden-4-yl, fluoren-2-yl, fluoren-3-yl, fluoren-9-yl and phenanthren-3-yl;
- b) C3-C8 cycloalkyl, more particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-1-yl, cuban-1-yl, bicyclo[4.4.0]decan-2-yl and cyclooctyl.
- Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical for D1 and D3 denotes for example:
- a) non-aromatic, saturated or partially unsaturated, 4-, 5- or 6-membered heterocyclyl, containing one to four nitrogen atoms and/or one or two oxygen atoms, more particularly 1-azacyclobut-1-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 4,5-dihydro-1,3-oxazol-2-yl, 4,5-dihydro-1,3-oxazol-4-yl, 4,5-dihydro-1,3-oxazol-5-yl, 4, 5-dihydro-4H-1,3-oxazin-2-yl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-morpholinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 5H-tetrazol-5-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, 1-piperazinyl and 2-piperazinyl;
- b) 5-membered heteroaryl, containing one to four nitrogen atoms or one to three nitrogen atoms and/or one sulfur or oxygen atom: more particularly 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-isoxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,5-thiadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,3,4-thiatriazol-5-yl, 1H-(1,2,3)triazol-1-yl, 1H-(1,2,3)triazol-4-yl, 1H-(1,2,3)triazol-5-yl, 1H-(1,3,4)triazol-1-yl and 1H-(1,3,4)triazol-2-yl;
- c) 6-membered heteroaryl, containing one to three nitrogen atoms: more particularly 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.
- The stated linear or cyclic hydrocarbon radicals and heterocycles may be unsubstituted or substituted, the substituents being selected preferably from the group X. Preferred, depending on the respective chain size or ring size, are 1, 2, 3 or 4 substituents; in the case of halogen substituents, preference is also given to substitution up to the maximum possible number (persubstitution).
- Advantageous compounds of the formula (I) are those in which all of the symbols have advantageous definitions.
- The symbols in the formula (I) preferably have the following definitions:
- A1 is preferably a group D1-[Y2-D2-]m-.
- D1 is preferably a group phenyl, pyrimidin-5-yl, naphth-1-yl, naphth-2-yl, thien-2-yl, the stated radicals being unsubstituted or substituted one or more times by a group X.
- D2 is preferably a group phenylene-1,4-diyl, pyridine-2,5-diyl, pyrimidine-2,5-diyl or thiophene-2,5-diyl, the stated radicals being unsubstituted or substituted one or more times by a group X.
- Y1 is preferably ˜C(O)— or ˜CH2C(O)—, where ˜ denotes the bond to the group A1.
- Y2 is preferably a bond.
- A2 is preferably
- a) a group —OS(O)2OL or
- b) a group —NH—W.
- W is preferably
- a) a group ˜SO3L or
- b) a group D3-Y3—.
- Y3 is preferably a bond or a group ˜CH2OC(O)—, ˜OC(O)—, ˜S(O)2—, ˜C(O)— or ˜CH2—C(O)—, where ˜ denotes the bond to the group D3.
- D3 is preferably a group methyl, ethyl, prop-2-yl, pent-5-yl, cyclopropyl, 1,1-dimethylethyl, phenyl, thien-2-yl, furan-2-yl, imidazolidin-5-yl, pyrazin-5-yl, naphthalen-1-yl.
- A3 is preferably a group pentan-1-yl or hexan-1-yl.
- X is preferably identically or differently fluoro, chloro, hydroxyl, carboxyl, methyl, trifluoromethyl, methoxy, dimethylamino or oxo (═O).
- m is preferably 0 or 1.
- Z is preferably ˜O—.
- R1 is preferably C(O)OM.
- R2 is preferably H.
- R3 is preferably H or OH.
- R4 is preferably NHC(O)CH3.
- R5, R6 are preferably identically or differently OH or OC(O)CH3.
- L is preferably a cation.
- M is preferably methyl, ethyl or a cation.
- Preferred compounds of the formula (I) are those in which all of the symbols have the preferred definitions.
- Further-preferred sialic acid derivatives of the formula (I) are those of the formulae (Ia)-(Ih), where the symbols have the definitions and preferences indicated in the formula (I).
- Particularly preferred, moreover, are sialic acid derivatives of the formulae (Iaa)-(Iam), where the symbols have the definitions indicated in the formula (I):
- Especially preferred are sialic acid derivatives of the formulae (Iba)-(Ibj), where the symbols have the definitions indicated in the formula (I):
- Strongly preferred are sialic acid derivatives of the formulae (Ica)-(Icj), where the symbols have the definitions indicated in the formula (I):
- The sialic acid derivatives (I) of the invention are obtainable employing synthesis processes that are known in principle. The compounds are preferably obtained by the preparation processes of the invention which are elucidated in more detail below, especially by synthesis schemes I-VII:
- Intermediates for the preparation of sialic acid derivatives of the formula (I) may be prepared, for example, by synthesis schemes I to IV.
- Compounds of the formula (III) may be prepared, for example, by addition of hydrogen chloride onto the double bond in compound (II). By way of example, compound 5 was prepared.
- Compounds of the formula (IV) may be prepared, for example, by replacing the chlorine atom in compound (III) by the group Z1-A3. By way of example, compound 13 was prepared.
- Compounds of the formula (VI) may be prepared, for example, by opening the epoxide in compound (V) by means of the group Z1-A3. By way of example, compound 8 was prepared.
- Compounds of the formula (VIII) may be prepared, for example, by replacing the hydroxyl group in compound (VII) with an azide. By way of example, compound 34 was prepared. Sialic acid derivatives of the formula (I) may be prepared, for example, by synthesis schemes V to VII.
- Compounds of the sialic acid derivatives of the formula (I) may be prepared, for example, by reducing the azide in compounds of the formula (VI) and subsequently reacting the resultant amine with a carboxylic acid or a sulfonyl chloride. Any protecting groups present may be removed by known methods. By way of example, compounds 10, 11, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 and 65 were prepared.
- Compounds of the sialic acid derivatives of the formula (I) may be prepared, for example, by reducing the azide in compounds of the formula (IV) and subsequently reacting the resultant amine with an activated carboxylic acid, a sulfonyl chloride or a sulfating agent. Any protecting groups present may be removed by methods that are common knowledge. By way of example, compounds 15, 16, 17, 18, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 and 64 were prepared.
- Compounds of the formula (I) may be prepared, for example, by reducing the azide in compounds of the formula (VIII) and subsequently reacting the resultant amine with an activated carboxylic acid, a sulfonyl chloride or a sulfating agent. Any protecting groups present may be removed by methods that are common knowledge. By way of example, compound 36 was prepared.
- The sialic acid derivatives of the formula (I) are suitable as pharmacologically active compounds and active ingredients for medicament preparations. They act as Siglec ligands, more particularly as Siglec-2 (CD22) ligands, for the regulation of the immune system, more particularly as an auxiliary in vaccinations, and also for the treatment of diseases whose course or activity can be influenced by the Siglec ligands, more particularly allergies, autoimmune disorders, chronic inflammations, paraplegia, multiple sclerosis, cancer, viral disorders, for example AIDS, and also in bacterial diseases, for example streptococci, parasitic disorders, for example Chagas disease, diseases in which the immune response is disrupted in the context of B cell activation, such as Common Variable Immunodeficiency (CVID) and IgA deficiency, in diseases of the hematopoietic organs and of the blood, and also in cancer, for example lymphomas and myelomas. Preferred indications are allergies, autoimmune disorders and CVID.
- Treatment in the sense of the invention denotes a therapeutic treatment, both for curing and also for the alleviation of symptoms, and also a preventive treatment.
- The sialic acid derivatives may be used in combination with other pharmacologically active substances, more particularly those which boost the activity of the compounds of the invention.
- The invention also provides a method for treating a Siglec-mediated disease, more particularly from the group of allergies, autoimmune disorders, chronic inflammations, paraplegia, multiple sclerosis, cancer, viral disorders, for examples AIDS, diseases in which the immune response is disrupted in the context of B cell activation, such as Common Variable Immunodeficiency (CVID) and IgA deficiency, by administering to a person affected by the disease a preferably therapeutically effective amount of a sialic acid derivative of the formula (I).
- Further provided by the invention is a sialic acid derivative of the formula (I) or a pharmacologically tolerated salt thereof as medicament, more particularly for the treatment of Siglec-mediated diseases, such as those described above.
- The invention provides, furthermore, a sialic acid derivative of the formula (I) or a pharmacologically tolerated salt thereof for use in a method for treating Siglec-mediated diseases, more particularly those described above.
- Additionally provided by the invention is a sialic acid derivative of the formula (I) for use in the production of a medicament for the treatment of Siglec-mediated diseases, more particularly those described above.
- Likewise provided by the invention is a pharmaceutical preparation (i.e. medicament) comprising at least one sialic acid derivative of the formula (I), or a pharmacologically tolerated salt thereof, and a pharmacologically tolerated carrier.
- The dose that is necessary to achieve a corresponding activity in treatment or prophylaxis is commonly dependent on the compound to be administered, the patient, the nature and severity of the disease or condition, and the nature and frequency of administration, and is within the discretion of the physician to be treated. In the case of intravenous administration, the dose may appropriately be in the range from 0.1 to 1000 mg, preferably 0.5 to 500 mg, and for oral administration in the range from 1 to 1000 mg, preferably 10 to 500 mg, in each case one or more times daily. For this purpose, the compounds of the formula (I) according to the invention, optionally in combination with other active substances, may be processed together with one or more inert customary excipients and/or diluents, as for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into customary pharmaceutical preparations such as tablets, film tablets, capsules, powders, solutions, suspensions or suppositories.
- The sialic acid derivatives (I) of the invention may be administered by any conventional method, including orally and parenterally, by means of intravenous, subcutaneous or intramuscular injections, for example.
- The sialic acid derivatives (I) may also be used for purposes other than those specified, for example as diagnostic agents, as for example in methods for determining the activity of Siglec ligands, as biochemical probes, or as intermediates for the preparation of further compounds, more particularly of pharmacologically active compounds.
- The invention is illustrated, but not restricted, by the examples.
- A. Synthesis examples are represented in Schemes 1 to 18.
- The compounds were obtained as described below:
- All of the compounds used but not described were purchased or prepared by known literature protocols.
- For purifications with silica gel, silica gel Si60 43-60 mm was used. Around 100 g of silica gel were utilized per gram of substance. Indicated in parentheses is the eluent. For purifications on RP-18 silica gel (YMC CO LTD., YMC ODS-AQ), the gel was suspended in methanol, introduced into a column, prewashed with water, and the substance was applied as a solution or suspension with water. The column volume was about 5 cm in height and about 1 cm in diameter. The solvent was forced through the column at low pressure, generated by a hand-operated pressure ball. The eluent used was a gradient from water to ethanol, unless otherwise indicated.
- Solvents were removed by means of a vacuum rotary evaporator under reduced pressure with a bath temperature of 40° C. In the syntheses hereinafter, this workstep is identified as “concentration”.
- All of the substances were lyophilized from water or a water/dioxane mixture.
- The reactions and substances were monitored by thin-layer chromatography. This was done using aluminum plates coated with silica gel, with a fluorescence indicator (Merck TLC Silica gel 60 F254). Substance detection took place under UV light at 366 and 254 nm. The chromatograms were subsequently sprayed with dilute sulfuric acid and heated in order to visualize the substances. For their detection, amines were visualized by spraying with ninhydrin solution and heating. Details and further visualization methods are elucidated in “Anfärbereagenzien für Dünnschicht- and Papierchromatographie” Merck, 1970. Spectroscopic data were recorded using Bruker ApexQe hybrid 9.4 T FT-ICR (ESI) and Varian 500 MHz or 300 MHz system (NMR) instruments.
-
- DMF N,N-dimethylformamide
- DIPEA N,N-diisopropylethylamine
- EtOH ethanol
- HAc acetic acid
- HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
- MeOH methanol
- TEA triethylamine
- Compound 1
- prepared according to: Tetrahedron Letters, 1994, 50 (25), 7445-7460
- Compound 4
- A solution of 2.2 g of compound 1 in 100 ml of MeOH was admixed with 4.45 g of triphenylphosphine and 6 ml of H2O and the suspension was stirred at room temperature for 18 h. With stirring, 20 ml of 20% strength acetic acid and 90 ml of H2O were added, the mixture was stirred for half an hour, the suspension was concentrated to 100 ml, and the concentrate was extracted with three times 100 ml of dichloromethane. The aqueous phase was lyophilized. Yield: 2.67 g of solid
- Compound 3
- A solution of 2.0 g of compound 2 in 20 ml of DMF was mixed with 1.69 g of 4-nitrophenyl 4-biphenylcarboxylate and 2.09 ml of TEA and stirred for 17 h. The solution was concentrated and the residue was purified on a silica gel column (CHCl3:MeOH gradient). Yield: 3.2 g
- Compound 4
- A solution of 2.2 g of compound 3 in 20 ml of acetic acid and 20 ml of acetic anhydride was admixed at 0° C. with 2 ml of concentrated sulfuric acid and stirred at 25° C. for 48 h. The acetic acid was removed on a rotary evaporator and the remaining solution was added slowly dropwise to 1000 ml of saturated sodium hydrogencarbonate solution. The suspension was stirred for 4 h and extracted with three times 200 ml of ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column (CH2Cl2:MeOH gradient). Yield: 2.0 g
- Compound 5
- A solution of 1.25 g of compound 4 and 1.19 ml of trimethylsilyl azide in 20 ml of dry tert-butanol was stirred at 80° C. for 4 h. The solution was concentrated and the residue was used further without further purification.
- Compound 6
- A solution of 1350 mg of compound 5 in 0.8 ml of acetonitrile and 2 ml of water was mixed at 60° C. with 538 mg of N-iodosuccinimide, stirred for 30 min and concentrated. The residue was purified on a silica gel column (CHCl3 to MeOH). Yield: 1170 mg.
- Compound 7
- A solution of 1140 mg of compound 6 in 10 ml of dry acetonitrile was mixed with 0.277 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, stirred for 15 min and concentrated. The residue was purified on a silica gel column (CHCl3 to MeOH). Yield: 750 mg
- Compound 8
- A solution of 20 mg of camphorsulfonic acid in 0.5 ml of ethyl 6-hydroxyhexanoate was mixed with 150 mg of compound 7, stirred for 20 min and diluted with 30 ml of CH2Cl2. The excess of ethyl 6-hydroxyhexanoate was removed on a silica gel column (CH2Cl2:MeOH 100:1). The product was eluted from the column (CH2Cl2:MeOH 10:1) and purified on RP18. Yield: 50 mg
- Compound 9
- A solution of 50 mg of compound 8 in 5 ml of MeOH was mixed with 0.05 ml of H2O and 51 mg of triphenylphosphine and stirred for 17 h. The solution was admixed with 0.5 ml of acetic acid (20%) and 10 ml of H2O, and the suspension was purified on RP18 (H2O, then dilute HCl pH3, then H2O to EtOH gradient). Yield: 40 mg
- Compounds 10
- A solution of 15 mg of compound 9 in 0.5 ml of DMF was admixed with 33 ml of DIPEA and 5.0 ml of propanoic anhydride, stirred for 15 min, diluted with 2 ml of H2O, admixed with 0.1 ml of 2M NaOH and stirred for 2 h. The solution was adjusted to pH 8-9 with 20% acetic acid, admixed with 0.5 ml of saturated Na2CO3 solution and purified on RP18. Yield: 9 mg; 1H NMR (500 MHz, CD3OD): d ppm 7.94 (d, J=8.63 Hz, 2H), 7.73 (d, J=8.38 Hz, 2H), 7.68 (dd, J=8.19, 1.17 Hz, 1H), 7.47 (t, J=7.66 Hz, 2H), 7.38 (t, J=7.39 Hz, 1H), 4.08 (ddd, J=8.41, 7.81, 3.14 Hz, 1H), 4.03 (dd, J=10.86, 10.03 Hz, 1H), 3.98 (t, J=10.27 Hz, 1H), 3.85 (td, J=9.04, 6.85 Hz, 1H), 3.81 (dd, J=9.97, 1.89 Hz, 1H), 3.78 (dd, J=13.59, 3.02 Hz, 1H), 3.59 (dd, J=13.88, 7.80 Hz, 1H), 3.55 (td, J=9.19, 7.08 Hz, 1H), 3.50 (d, J=10.24 Hz, 1H), 3.43 (dd, J=9.00, 2.00 Hz, 1H), 2.22 (q, J=7.63 Hz, 2H), 2.17 (dd, J=8.24, 7.03 Hz, 2H), 1.90 (s, 3H), 1.66-1.57 (m, 4H), 1.44-1.35 (m, 2H), 1.13 (t, J=7.65 Hz, 3H); HRMS (ESI-neg) calculated for C33H41N3O12 [M-2Na+H]−: 672.2774, found: 672.2801.
- Compound 11
- A solution of 24 mg of compound 9 in 1 ml of CH2Cl2 was admixed with 21 μl of TEA and 3.6 μl of methanesulfonyl chloride and stirred for 15 min. The solution was admixed with 2 ml of saturated NaHCO3 solution, stirred for 15 min, admixed with 20 ml of CH2Cl2 and 20 ml of saturated NaHCO3. The organic phase was dried (MgSO4), filtered and purified on RP18. The residue was dissolved in a little EtOH. The solution was admixed with water until turbidity appeared, adjusted with 2M NaOH to pH 12-13, stirred for 2 h, neutralized with dilute acetic acid and concentrated. The residue was dissolved with a little water, admixed with 0.3 ml of saturated NaHCO3 and purified on RP18. Yield: 11 mg; 1H NMR (500 MHz, CD3OD): δ ppm 7.94 (d, J=8.68 Hz, 2H), 7.73 (d, J=8.70 Hz, 2H), 7.68 (dd, J=8.41, 1.23 Hz, 2H), 7.47 (t, J=7.62 Hz, 2H), 7.38 (t, J=7.39 Hz, 1H), 4.08 (ddd, J=9.06, 7.59, 3.21 Hz, 1H), 3.87 (t, J=10.48 Hz, 1H), 3.85 (td, J=9.22, 6.53 Hz, 1H), 3.77 (dd, J=13.73, 3.14 Hz, 1H), 3.75 (dd, J=10.49, 2.06 Hz, 1H), 3.59 (dd, J=13.75, 7.59 Hz, 1H), 3.54 (td, J=9.08, 6.72 Hz, 1H), 3.47 (d, J=10.44 Hz, 1H), 3.44 (dd, J=8.99, 1.98 Hz, 1H), 3.34 (t, J=10.45 Hz, 1H), 3.05 (s, 3H), 2.16 (dd, J=8.22, 7.14 Hz, 2H), 1.98 (s, 3H), 1.66-1.57 (m, 4H), 1.45-1.35 (m, 2H); HRMS (ESI-neg) calculated for C31H39N3O13S [M-2Na+H]−: 694.2287, found: 694.2302.
- Compounds 12
- A solution of 70 mg of compound 5 in 10 ml of acetyl chloride was admixed at 0° C. with 0.5 g of LiCl, and 0.5 ml of HCl (37%) was added dropwise over the course of 1 h. The solution was stirred at 0° C. for 5 h and admixed with LiCl to saturation point. The suspension was stirred at RT for 5 days, and every 20 h it was cooled to 0° C., 0.1 ml of HCl (37%) was added dropwise and then the suspension was stirred at 0° C. for 4 h. The suspension was concentrated, the residue was admixed with CH2Cl2, the suspension was washed with cold NaHCO3 solution and with saturated NaCl solution, dried (MgSO4), filtered and concentrated. The residue was used directly without storage.
- Compound 13
- A mixture of 2 ml of CH2Cl2, 2 ml of ethyl 6-hydroxyhexanoate and 0.5 g of dry molecular sieve A4 was mixed with 50 mg of compound 12 and stirred for 5 days. CH2Cl2 was removed under reduced pressure, the suspension was stirred at 40° C. for 1 h and diluted with CH2Cl2. Ethyl 6-hydroxyhexanoate was removed on a silica gel column (CH2Cl2:MeOH 100:1), and the products were eluted from the column (CH2Cl2:MeOH 5:1) and concentrated. The residue was purified on RP18. Yield: 20 mg
- Compound 14
- A solution of 20 mg of compound 13 in 5 ml of MeOH and 0.2 ml of HAc (20%) was admixed with a catalytic amount of Pd-on-carbon and hydrogenated for 60 min. The suspension was filtered over Celite, concentrated and lyophilized. Yield: 16 mg
- Compound 15
- A solution of 16 mg of compound 14 in 1 ml of DMF was admixed with 13 mg of sulfur trioxide-pyridine (1:1) and 58 μl of TEA, stirred for 20 min, admixed with MeOH and stirred for a further 20 min. The excess TEA was removed under reduced pressure and the solution was diluted with water, adjusted to pH 8 with saturated NaHCO3 and purified on RP18. The product was dissolved with a little EtOH, and the solution was diluted with water until turbidity occurred, adjusted to a pH of 13 using 2M NaOH, stirred for 2 h, diluted with 10 ml of water, adjusted to a pH of 8 with dilute acetic acid, and purified on RP18. Yield: 4 mg; 1H NMR (500 MHz, CD3OD): δ ppm 7.94 (d, J=8.45 Hz, 2H), 7.73 (d, J=8.53 Hz, 2H), 7.68 (dd, J=8.33, 1.11 Hz, 2H), 7.47 (t, J=7.68 Hz, 2H), 7.38 (t, J=7.39 Hz, 1H), 4.08 (ddd, J=8.82, 7.94, 3.21 Hz, 1H), 3.79 (td, J=9.10, 6.96 Hz, 1H), 3.78 (dd, J=13.54, 3.23 Hz, 1H), 3.71 (dd, J=10.22, 1.90 Hz, 1H), 3.61 (t, J=10.20 Hz, 1H), 3.58 (dd, J=13.66, 7.75 Hz, 1H), 3.47 (td, J=9.05, 7.02 Hz, 1H), 3.45 (dd, J=9.05, 1.94 Hz, 1H), 3.39 (ddd, J=12.12, 10.61, 4.41 Hz, 1H), 3.07 (dd, J=12.68, 4.54 Hz, 1H), 2.16-2.12 (m, 2H), 2.01 (s, 3H), 1.65-1.52 (m, 5H), 1.40-1.32 (m, 2H); HRMS (ESI-neg) calculated for C30H36N3Na3O13S [M-3Na+2H]−: 680.2131, found: 680.2153.
- Compound 16
- A solution of 65 mg of compound 14 in 1 ml of DMF was admixed with 12 μl of propanoic anhydride and 35 μl of TEA, stirred for 1 h and concentrated. The residue was purified on RP18. Yield: 60 mg; 1H NMR (500 MHz, CD3OD): δ ppm 7.89 (d, J=8.55 Hz, 2H), 7.65 (d, J=8.56 Hz, 2H), 7.60 (dd, J=8.30, 1.22 Hz, 2H), 7.45 (t, J=7.54 Hz, 2H), 7.38 (t, J=7.36 Hz, 1H), 7.10 (dd, J=8.03, 4.48 Hz, 1H), 5.76 (d, J=8.03 Hz, 1H), 5.69 (d, J=9.33 Hz, 1H), 5.31 (td, J=9.69, 3.31 Hz, 1H), 5.22 (dd, J=9.73, 2.13 Hz, 1H), 4.29 (ddd, J=15.04, 8.20, 3.13 Hz, 1H), 4.10 (q, J=7.13 Hz, 2H), 4.10 (dd, J=10.08, 2.24 Hz), 3.99-3.88 (m, 2H), 3.78 (td, J=9.39, 6.28 Hz, 1H), 3.77 (s, 3H), 3.21 (td, J=9.41, 6.39 Hz, 1H), 3.06 (td, J=15.07, 4.12 Hz, 1H), 2.57 (dd, J=12.82, 3.58 Hz, 1H), 2.29 (t, J=7.73 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 1.89 (s, 3H), 1.72 (t, J=12.64 Hz, 1H), 1.67-1.60 (m, 2H), 1.58-1.52 (m, 2H), 1.44-1.32 (m, 2H), 1.24 (t, J=7.14 Hz, 3H), 1.09 (t, J=7.60 Hz, 3H); HRMS (ESI-pos) calculated for C40H53N3O13 [M+Na]+: 806.3471, found: 806.3492.
- Compound 17
- A solution of 30 mg of compound 16 in a little EtOH was admixed with water until turbidity occurred, adjusted to a pH of 12-13 using 2M NaOH, and maintained at said pH for 2 h. The solution was diluted with 10 ml of water, adjusted to a pH of 8-9 using dilute acetic acid and purified on RP18. Yield: 24 mg; 1H NMR (500 MHz, CD3OD): δ ppm 7.94 (d, J=8.61 Hz, 2H), 7.72 (dd, J=8.69, 1.85 Hz, 2H), 7.67 (dd, J=6.95, 1.46 Hz, 2H), 7.46 (t, J=7.61 Hz, 2H), 7.38 (t, J=7.39 Hz, 1H), 4.11-4.02 (m, 2H), 3.84-3.76 (m, 4H), 3.60 (dd, J=13.57, 7.35 Hz, 1H), 3.51-3.44 (m, 2H), 2.67 (dd, J=12.43, 4.40 Hz, 1H), 2.20-2.12 (m, 4H), 1.91 (s, 3H), 1.66 (t, J=12.56 Hz, 1H), 1.64-1.53 (m, 4H), 1.41-1.33 (m, 2H), 1.11 (t, J=7.66 Hz, 3H); HRMS (ESI-neg) calculated for C33H41N3Na2O11[M-2Na+H]−: 656.2825, found: 656.2815.
- Compound 18
- A solution of 20 mg of compound 14 in 1 ml of DMF was admixed with 5 mg of succinic anhydride and 21 μl of TEA, stirred for 30 min and concentrated. The residue was purified on RP18. Yield: 17 mg; 1H NMR (300 MHz, CD3OD): δ ppm 7.84 (d, J=8.36 Hz, 2H), 7.71 (d, J=8.26 Hz, 2H), 7.65 (d, J=7.46 Hz, 2H), 7.46 (t, J=7.45 Hz, 2H), 7.37 (t, J=7.27 Hz, 1H), 5.44 (ddd, J=9.36, 6.87, 2.61 Hz, 1H), 5.26 (dd, J=9.25, 2.13 Hz, 1H), 4.20 (dd, J=10.13, 1.95 Hz, 1H), 4.09 (q, J=7.11 Hz, 2H), 3.95-3.73 (m, 7H), 3.37 (dd, J=14.53, 6.89 Hz, 1H), 3.23 (td, J=9.56, 6.28 Hz, 1H), 2.44 (dd, J=13.07, 2.97 Hz, 1H), 2.29 (t, J=7.39 Hz, 2H), 2.17 (s, 2H), 2.12 (s, 2H), 1.85 (s, 3H), 1.75 (t, J=12.75 Hz, 1H), 1.67-1.47 (m, 4H), 1.45-1.30 (m, 4H), 1.22 (t, J=7.12 Hz, 3H); HRMS (ESI-neg) calculated for C41H52N3NaO15 [M-Na]−: 826.3404, found: 826.3381.
- Compound 20
- A solution of 25 mg of compound 19 (WO 2013097942) in water was adjusted to a pH of 13 using 2M NaOH, held at that pH for 2 h, adjusted to a pH of 8 using dilute HAc and purified on RP18. The lyophilized product (20 mg) was dissolved in 0.5 ml of DMF and admixed in portions with sulfur trioxide-pyridine (1:1) until only about 20% of reactant was detectable in the TLC. MeOH was added, stirring took place for 30 min, and the MeOH was removed under reduced pressure. The solution was diluted with water, adjusted to a pH of 8 using NaHCO3 solution and purified on RP18. Yield: 5 mg (21%)1H NMR (500 MHz, CD3OD): δ ppm 7.94 (d, J=8.63 Hz, 2H), 7.73 (d, J=8.62 Hz, 2H), 7.68 (dd, J=8.38, 1.21 Hz, 2H), 7.47 (t, J=7.66 Hz, 2H), 7.38 (t, J=7.40 Hz, 1H), 4.46 (ddd, J=11.61, 9.99, 5.15 Hz, 1H), 4.09 (ddd, J=8.84, 7.74, 3.27 Hz, 1H), 3.87 (td, J=9.47, 6.40 Hz, 1H), 3.81 (t, J=10.23 Hz, 1H), 3.79 (dd, J=13.65, 3.28 Hz, 1H), 3.73 (dd, J=10.44, 1.89 Hz, 1H), 3.58 (dd, J=13.68, 7.55 Hz, 1H), 3.58 (td, J=9.49, 6.34 Hz, 1H), 3.46 (dd, J=8.96, 1.86 Hz, 1H), 3.19 (dd, J=12.26, 5.10 Hz, 1H), 2.73 (dd, J=8.03, 7.62 Hz, 2H), 2.59 (dt, J=7.14, 5.04 Hz, 2H), 2.40 (dd, J=8.02, 7.60 Hz, 2H), 2.00 (s, 3H), 1.85-1.79 (m, 2H), 1.71 (t, J=12.00 Hz, 1H); HRMS (ESI-neg) calculated for C30H35N2Na3O14S2 [M-3Na+2H]−: 713.1692, found: 713.1715.
- Compound 22
- Compound 21 (3500 mg) was dissolved in 20 ml of dry allyl alcohol, admixed with 5 g of ground molecular sieve A4 and stirred for 5 h. The suspension was concentrated at 40° C. and the residue was admixed with CH2Cl2, filtered over Celite and purified on a silica gel column (CH2Cl2 to MeOH). The isolated product was recrystallized from ethyl acetate/diethyl ether. Yield: 1600 mg
- Compound 23
- A solution of 1600 mg of compound 22 in 20 ml of dry MeOH was admixed with 1 ml of 1M sodium methoxide. Following complete reaction, the solution was neutralized with ion exchange resin (Dowex H+form) in MeOH. The resin was removed by filtration and the solution was concentrated. Yield: 1200 mg
- Compound 24
- A solution of 1200 mg of compound 23 in 20 ml of MeOH and 4 ml of water was admixed with 2010 mg of zinc powder and 1670 mg of ammonium chloride and stirred for 5 h. The suspension was filtered over Celite, concentrated and used further directly. Yield: 1200 mg
- Compound 25
- A solution of 1200 mg of compound 24 in 20 ml of MeOH was admixed with 721 mg of Boc anhydride and 0.49 ml of TEA, stirred for 2 h and concentrated. The residue was purified on silica gel (ethyl acetate). Yield: 976 mg
- Compound 26
- Compound 25 (976 mg) was dissolved three times in 10 ml of dry DMF and concentrated under reduced pressure. The anhydrous residue was dissolved in 10 ml of dry DMF and admixed at 0° C. with 517 mg of dry lithium azide, 1678 mg of tetrabromomethane and 664 mg of triphenylphosphine. The solution was stirred at 25° C. for 16 h, admixed with 5 ml of MeOH and concentrated. The residue was admixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated NaCl, dried (MgSO4), filtered and purified on a silica gel column (ethyl acetate). Yield: 700 mg
- Compound 27
- A solution of 700 mg of compound 26 in 50 ml of DMF was admixed with 0.5 ml of water, 1130 mg of triphenylphosphine and 1375 mg of 4-nitrophenyl 4-biphenylcarboxylate, stirred for three days, concentrated and purified on a silica gel column (CH2Cl2 to MeOH). Yield: 440 mg
- Compound 28
- A solution of 30 mg of compound 27 in 5 ml of MeOH and 2 ml of water was flushed with nitrogen for 20 min, admixed with 41 μl of thiopropionic acid and a catalytic amount of azaisobutyronitrile, and irradiated with UV light for 12 h. The solution was concentrated and the residue was purified on RP18. Yield: 30 mg; 1H NMR (500 MHz, CD3OD): δ ppm 7.93 (d, J=8.62 Hz, 2H), 7.71 (d, J=8.65 Hz, 2H), 7.66 (dd, J=8.38, 1.21 Hz, 2H), 7.45 (t, J=7.62 Hz, 2H), 7.37 (t, J=7.39 Hz, 1H), 4.05 (ddd, J=8.87, 7.28, 3.21 Hz, 1H), 3.91-3.82 (m, 6H), 3.80 (dd, J=13.83, 3.23 Hz, 1H), 3.67-3.62 (m, 1H), 3.60 (dd, J=13.78, 7.35 Hz, 1H), 3.49 (td, J=9.37, 6.42 Hz, 1H), 3.45 (dd, J=8.83, 1.25 Hz, 1H), 2.71 (dd, J=8.46, 7.06 Hz, 2H), 2.62-2.51 (m, 3H), 2.39 (dd, J=8.56, 6.84 Hz, 2H), 1.90 (s, 3H), 1.82-1.70 (m, 3H), 1.42 (s, 9H); HRMS (ESI-neg) calculated for C36H48N3NaO12S [M-Na]−: 746.2964, found: 746.2928.
- Compound 29
- A solution of 30 mg of compound 28 in a little MeOH was admixed with water until turbidity occurred, adjusted to a pH of 13 using 2M NaOH, stirred at the pH for 2 h, adjusted to a pH of 8-9 using dilute acetic acid, and purified on RP18. Yield: 25 mg; 1H NMR (500 MHz, CD3OD): δ ppm 7.93 (d, J=8.61 Hz, 2H), 7.71 (d, J=8.63 Hz, 2H), 7.66 (dd, J=8.37, 1.19 Hz, 2H), 7.45 (t, J=7.63 Hz, 2H), 7.36 (t, J=7.39 Hz, 1H), 4.06 (ddd, J=8.96, 7.60, 3.17 Hz, 1H), 3.87 (td, J=9.48, 6.39 Hz, 1H), 3.80-3.66 (m, 4H), 3.57 (dd, J=13.22, 6.98 Hz, 1H), 3.54 (td, J=9.48, 6.25 Hz, 1H), 3.44 (dd, J=8.99, 1.24 Hz, 1H), 2.72 (dd, J=8.51, 6.99 Hz, 12H), 2.68 (dd, J=12.56, 3.65 Hz, 1H), 2.63-2.52 (m, 2H), 2.40 (dd, J=8.51, 7.12 Hz, 2H), 1.92 (s, 3H), 1.83-1.76 (m, 2H), 1.61 (t, J=12.16 Hz, 1H), 1.42 (s, 9H); HRMS (ESI-neg) calculated for C36H45N3Na2O12S [M-2Na+H]−: 732.2808, found: 732.2763.
- Compound 30
- A solution of 3500 mg of compound 21 in 4 ml of CH2Cl2 was stirred together with 1.9 ml of ethyl 6-hydroxyhexanoate and 5 g of dry molecular sieve A4, and CH2Cl2 was removed on a rotary evaporator. The suspension was stirred at 40° C. for 6 h, diluted with CH2Cl2 and filtered over Celite. Ethyl 6-hydroxyhexanoate was removed on a silica gel column (CH2Cl2:MeOH 100:1). The products were eluted from the column with (CH2Cl2:MeOH 5:1) and again purified on silica gel (CH2Cl2 to MeOH). Yield 2300 mg of unclean product, which was used further without additional purification.
- Compound 31
- A solution of 2300 mg of compound 30 in 20 ml of dry MeOH was admixed with fresh sodium methoxide in MeOH until pH indicator paper indicated a pH of 8-9. After 1 h the solution was neutralized with ion exchange resin (Dowex H+form) in MeOH. The resin was removed by filtration, the solution was concentrated and the residue was purified on a silica gel column (CH2Cl2 to MeOH). The fractions containing product were purified on RP18. Yield: 374 mg
- Compound 32
- A solution of 370 mg of compound 31 in 10 ml of MeOH was admixed with 0.5 ml of acetic acid (20%) and a catalytic amount of Pd-on-carbon and hydrogenated for 2 h. The suspension was filtered over Celite, the solution was concentrated and the residue was lyophilized. Yield: 395 mg
- Compound 33
- A solution of 395 mg of compound 32 in 10 ml of DMF was admixed with 142 mg of benzyloxycarbonyl chloride and 0.31 ml of TEA, stirred for 2 h and concentrated. The residue was purified on a silica gel column (CH2Cl2 to MeOH). Yield: 245 mg
- Compound 34
- Compound 33 (245 mg) was dissolved three times in 10 ml of dry DMF and concentrated under reduced pressure. The anhydrous residue was dissolved in 10 ml of dry DMF and admixed at 0° C. with 100 mg of dry lithium azide, 325 mg of tetrabromomethane and 139 mg of triphenylphosphine. The solution was stirred at 25° C. for 16 h, admixed with 5 ml of MeOH and concentrated. The residue was admixed with water and was extracted twice with toluene and twice with ethyl acetate. The combined ethyl acetate phases were dried (MgSO4), filtered and purified on RP18. Yield: 176 mg
- Compound 35
- A solution of 175 mg of compound 34 in 10 ml of MeOH and 2 ml of water was admixed with 182 mg of zinc powder and 151 mg of ammonium chloride and stirred for 2 h. The suspension was filtered over Celite, concentrated and used further directly. Yield: 270 mg
- Compound 36
- A solution of 55 mg of compound 35 and 28 mg of 4-(4-fluorophenyl)benzoic acid in 0.5 ml of DMF was admixed with 49 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium and 0.146 ml of DIPEA. The solution was stirred for 10 min and concentrated and the residue was purified over RP18. Yield 40 mg
- Compound 37
- A solution of 40 mg of compound 36 in 5 ml of MeOH and 0.5 ml of HAc (20%) was admixed with a catalytic amount of Pd-on-carbon and hydrogenated for 60 min. The suspension was filtered over Celite, concentrated and lyophilized. The residue (30 mg) was dissolved in 2 ml of DMF and admixed with 20 mg of sulfur trioxide-pyridine (1:1) and 59 μl of TEA. The solution was stirred for 60 min, admixed with 5 ml of water and 0.5 ml of 2M NaOH and stirred for a further 40 min, neutralized with HAc and concentrated. The residue was dissolved in water, admixed with 1 ml of saturated Na2CO3 and purified on RP18. Yield: 8 mg; 1H NMR (500 MHz, CD3OD): δ ppm 7.92 (d, J=8.54 Hz, 2H), 7.71-7.67 (m, 4H), 7.19 (t, J=8.84 Hz, 2H), 4.06 (ddd, J=9.19, 8.27, 3.20 Hz, 1H), 3.80-3.73 (m, 2H), 3.69 (dd, J=10.20, 1.94 Hz, 1H), 3.60 (dd, J=10.84, 9.69 Hz, 1H), 3.56 (dd, J=13.66, 7.80 Hz, 1H), 3.46 (td, J=8.94, 6.86 Hz, 1H), 3.43 (dd, J=8.96, 1.93 Hz, 1H), 3.37 (ddd, J=12.25, 10.61, 4.49 Hz, 1H), 3.05 (dd, J=12.71, 4.53 Hz, 1H), 2.13 (dd, J=8.02, 7.36 Hz, 2H), 2.00 (s, 3H), 1.62-1.51 (m, 5H), 1.38-1.31 (m, 2H); HRMS (ESI-neg) calculated for C30H35FN3Na3O13S [M-2Na+H]−: 720.1889, found: 720.1856.
- Compounds 38, 39, 40, 41, 42
- General procedure: A solution of 0.20 mg of compound 9 in 50 μl of DMF was admixed with a 25-fold excess of the corresponding anhydride and 100-fold excess of DIPEA. The solution was stirred at 20° C. for 10 min. The reaction was monitored by thin-layer chromatography and was quantitative for all the experiments. The solution was diluted with 500 μl of water, admixed with 50 μl of 2M NaOH and, after 2 h, was admixed with 50 μl of HAc (20%) and lyophilized. Following the addition of acetic acid, the reaction was monitored by thin-layer chromatography and was quantitative for all the experiments.
- Compounds 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64
- General procedure: A solution of 0.20 mg of compound 9 in 50 μl of DMF was admixed with a 25-fold excess of the corresponding carboxylic acid, a 15-fold excess of HATU and 100-fold excess of DIPEA and the solution was stirred at 20° C. for 10 min. The reaction was monitored by thin-layer chromatography and was quantitative for all the experiments. The solution was diluted with 500 μl of water, admixed with 50 μl of 2M NaOH and, after 2 h, was admixed with 50 μl of HAc (20%) and lyophilized. Following the addition of acetic acid, the reaction was monitored by thin-layer chromatography and was quantitative for all the experiments.
- Compounds 65
- A solution of 0.20 mg of compound 9 in 50 μl of DMF was admixed with a 25-fold excess of dansyl chloride and 100-fold excess of DIPEA and the solution was stirred at 20° C. for 10 min. The reaction was monitored by thin-layer chromatography and was quantitative. The solution was diluted with 500 μl of water, admixed with 50 μl of 2M NaOH and, after 2 h, was admixed with 50 μl of HAc (20%) and lyophilized. Following the addition of acetic acid, the reaction was monitored by thin-layer chromatography and was quantitative.
- Compounds 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76
- General procedure: A solution of 0.20 mg of compound 35 in 50 μl of DMF was admixed with a 25-fold excess of the corresponding carboxylic acid, a 15-fold excess of HATU and 100-fold excess of DIPEA and the solution was stirred at 20° C. for 10 min. The reactions were monitored by thin-layer chromatography and was quantitative for all the experiments. The solution was diluted with 500 μl of water, admixed with 50 μl of 2M NaOH and, after 2 h, was admixed with 50 μl of HAc (20%) and lyophilized. Following the addition of acetic acid, the reaction was monitored by thin-layer chromatography and was quantitative for all the experiments.
- Compound 77
- A solution of 40 mg of compound 27 in 5 ml of MeOH and 2 ml of water was flushed with nitrogen for 20 min, admixed with 705 mg of cysteamine hydrochloride and a catalytic amount of azaisobutyronitrile, and irradiated with UV light for 12 h. The solution was concentrated and the residue was purified on RP18. Yield: 407 mg; 1H NMR (500 MHz, CD3OD): δ ppm 7.93 (d, J=8.64 Hz, 2H), 7.72 (d, J=8.66 Hz, 2H), 7.66 (dd, J=8.38, 1.23 Hz, 2H), 7.46 (t, J=7.60 Hz, 2H), 7.38 (t, J=7.38 Hz, 1H), 4.07 (ddd, J=8.67, 7.73, 3.08 Hz, 1H), 3.93 (dd, J=13.76, 2.91 Hz, 1H), 3.92 (ddd, J=9.63, 7.03, 5.02 Hz, 1H), 3.88-3.84 (m, 1H), 3.86 (s, 3H), 3.82 (dd, J=10.34, 1.28 Hz, 1H), 3.47 (dd, J=8.76, 1.42 Hz, 1H), 3.47-3.43 (m, 1H), 3.43 (dd, J=13.83, 7.64 Hz, 1H), 3.14 (t, J=6.96 Hz, 1H), 3.14 (t, J=6.56 Hz, 1H), 2.80 (t, J=6.75 Hz, 2H), 2.64 (t, J=6.97 Hz, 2H), 2.55 (dd, J=12.94, 4.00 Hz, 1H), 1.93 (s, 3H), 1.86-1.71 (m, 3H), 1.43 (s, 9H); HRMS (ESI-neg) calculated for C36H48N3NaO12S [M-Na]−: 719.3320, found: 719.3335.
- Biological Tests
- The biological activity of the substances was determined in an ELISA-based inhibition assay as described in “Eur. J. Immunol. 2012, 42, 2792-2802”. The sialic acid derivatives of the formula (I) inhibit the binding of soluble CD22 to immobilized IgM in proportion to their affinity for CD22. The soluble CD22 protein was expressed in the CHO-Lec1 cell line and isolated as described by “Eur. J. Immunol. 2012, 42, 2792-2802”. The known substance “BPCNeu5Ac” (J. Exp. Med. 2002, 195, 1207-1213) was co-tested in the assays as a reference. The increase in affinity is reported as rIP (relative inhibitory affinity).
- Table I shows the affinity or relative inhibitory potency (rIP) of the sialic acid derivatives of the formula (I).
- Further sialic acid derivatives of the formula (I) for which rIP values were determined are listed in Table II. As a reference, compound 10, a sialic acid derivative of the formula (I) with surprisingly high affinity, was co-tested in the same assay. The sialic acid derivatives of the formula (I) in Table II show an affinity level comparable with that of reference compound 10.
- Further sialic acid derivatives of the formula (I) for which rIP values were determined are listed in Table III. As a reference, compound 17, a sialic acid derivative of the formula (I) with surprisingly high affinity, was co-tested in the same assay. The sialic acid derivatives of the formula (I) in Table III show an affinity level comparable with that of reference compound 17.
- Further sialic acid derivatives of the formula (I) for which rIP values were determined are listed in Table IV. As a reference, compound 66 was co-tested in the same assay. The sialic acid derivatives of the formula (I) in Table IV show an affinity level comparable with that of reference compound 66.
- Table V shows sialic acid derivatives of the formula (I) which are suitable as prodrugs, their affinity for CD22 having not been determined, since the active molecule is liberated only in vivo by enzymatic cleavage.
Claims (16)
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ES2785551T3 (en) | 2014-06-30 | 2020-10-07 | Glykos Finland Oy | Saccharide derivative of a toxic payload and its conjugates with antibodies |
DE102017002810A1 (en) | 2017-03-22 | 2018-09-27 | Reinhard Brossmer | Sialic acid derivatives with C-C triple bond and their preparation |
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CA2878865A1 (en) | 2012-06-21 | 2013-12-27 | Reinhard Brossmer | Sialic acid derivatives |
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